by Keyword: 12/15-lipoxygenase
Schierwagen, R, Gu, WY, Brieger, A, Brüne, B, Ciesek, S, Dikic, I, Dimmeler, S, Geisslinger, G, Greten, FR, Hermann, E, Hildt, E, Kempf, VAJ, Klein, S, Koch, I, Mühl, H, Müller, V, Peiffer, KH, Kestner, RI, Piiper, A, Rohde, G, Scholich, K, Schulz, MH, Storf, H, Toptan, T, Vasa-Nicotera, M, Vehreschild, MJGT, Weigert, A, Wild, PJ, Zeuzem, S, Engelmann, C, Schaefer, L, Welsch, C, Trebicka, J, (2023). Pathogenetic mechanisms and therapeutic approaches of acute-to-chronic liver failure American Journal Of Physiology-Cell Physiology 325, C129-C140 
Liver cirrhosis is the end stage of all chronic liver diseases and contributes significantly to overall mortality of 2% globally. The age-standardized mortality from liver cirrhosis in Europe is between 10 and 20% and can be explained by not only the development of liver cancer but also the acute deterioration in the patient's overall condition. The development of complications including accumulation of fluid in the abdomen (ascites), bleeding in the gastrointestinal tract (variceal bleeding), bacterial infections, or a decrease in brain function (hepatic encephalopathy) define an acute decompensation that requires therapy and often leads to acute-on-chronic liver failure (ACLF) by different precipitating events. However, due to its complexity and organ-spanning nature, the pathogenesis of ACLF is poorly understood, and the common underlying mechanisms leading to the development of organ dysfunction or failure in ACLF are still elusive. Apart from general intensive care interventions, there are no specific therapy options for ACLF. Liver transplantation is often not possible in these patients due to contraindications and a lack of prioritization. In this review, we describe the framework of the ACLF-I project consortium funded by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) based on existing findings and will provide answers to these open questions.
JTD Keywords: 12/15-lipoxygenase, combination, inflammation, interleukin-22, metabolism, mortality, organ failure, portal-hypertension, receptor, regeneration, systemic inflammation, systems medicine, translational hepatology, Decompensated cirrhosis, Organ failure, Systemic inflammation, Systems medicine, Translational hepatology
Queck, A., Fink, A. F., Sirait-Fischer, E., Rüschenbaum, S., Thomas, D., Snodgrass, R. G., Geisslinger, G., Baba, H. A., Trebicka, J., Zeuzem, S., Weigert, A., Lange, C. M., Brüne, B., (2020). Alox12/15 deficiency exacerbates, while lipoxin A4 ameliorates hepatic inflammation in murine alcoholic hepatitis Frontiers in Immunology 11, 1447
Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15−/− mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15−/− mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15−/− mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.
JTD Keywords: Alcoholic hepatitis, Arachidonate 12/15-lipoxygenase (Alox12/15), Lipoxin A4, Resolution of inflammation, Specialized pro-resolving lipid mediators (SPMs)
